Anti-Leukemic Properties of Aplysinopsin Derivative EE-84 Alone and Combined to BH3 Mimetic A-1210477

Abstract

Aplysinopsins are a class of marine indole alkaloids that exhibit a wide range of biological activities. Although both the indole and N-benzyl moieties of aplysinopsins are known to possess antiproliferative activity against cancer cells, their mechanism of action remains unclear. Through in vitro and in vivo proliferation and viability screening of newly synthesized aplysinopsin analogs on myelogenous leukemia cell lines and zebrafish toxicity tests, as well as analysis of differential toxicity in noncancerous RPMI 1788 cells and PBMCs, we identified EE-84 as a promising novel drug candidate against chronic myeloid leukemia. This indole derivative demonstrated drug-likeness in agreement with Lipinski’s rule of five. Furthermore, EE-84 induced a senescent-like phenotype in K562 cells in line with its cytostatic effect. EE-84-treated K562 cells underwent morphological changes in line with mitochondrial dysfunction concomitant with autophagy and ER stress induction. Finally, we demonstrated the synergistic cytotoxic effect of EE-84 with a BH3 mimetic, the Mcl-1 inhibitor A-1210477, against imatinib-sensitive and resistant K562 cells, highlighting the inhibition of antiapoptotic Bcl-2 proteins as a promising novel senolytic approach against chronic myeloid leukemia.

Naturally derived indole alkaloids targeting regulated cell death (RCD) for cancer therapy: from molecular mechanisms to potential therapeutic targets

“…Accordingly, cell autophagy is closely associated with ER stress. EE-84 was shown to trigger ER stress and then promote K562 CML cell autophagy, which is accompanied by morphological changes as well as the activation of the PERK-eIF2α-ATF4-CHOP pathway [ 242 ]. These results indicate that EE84 has excellent antileukemic properties and is expected to be a potential drug for the treatment of leukemia.…”

“…As mentioned above, EE-84, as an aplysinopsin derivative, has potential antileukemic effects. In order to enhance its anticancer activity, the combination of EE-84 and the Mcl-1 inhibitor, A-1210477, was shown to cause apoptotic cell death in imatinib-sensitive and resistant K562 cells and activate the caspase cascade, producing a synergistic cytotoxic effect [ 242 ]. This combination method provides a research basis for the treatment of drug-resistant leukemia.…”

Involvement of Bcl-2 Family Proteins in Tetraploidization-Related Senescence

“…Other types of Bcl-2 family inhibitors that act as senolytic agents are small molecule Mcl-1 inhibitors such as A1210477 and S63845. A1210477 synergizes with EE-84, an aplysinopsin that induces a senescent phenotype in K562 cells [ 114 ]. Recently, it has been described that treatment with the Mcl-1 inhibitor S63845 leads to the complete elimination of senescent tumor cells and metastases [ 53 ].…”

Marine Compounds, Mitochondria, and Malignancy: A Therapeutic Nexus

“…Aplysinopsins, a marine indole alkaloid isolated from genera of sponges and scleractinian corals, has exhibited antiproliferative effects on in K562 cells. EE-84, one of the analogs of aplysinopsins, reduced cell proliferation, intake of oxygen, level of antiapoptotic protein, Bcl-2, and caused MMP loss in K562 cells [ 137 ]. Another natural product from the marine sponge and fungus, Aspergillus sp., 18B-15-3, has exhibited anticarcinoma properties in pancreatic cancer.…”